CN102887904A - 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof - Google Patents
2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative disclosed as Formula I, a synthesis method and application thereof in preparing medicines for inhibiting tumor cell activity. The 50% inhibition concentrations IC50 of the 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine-hydrochloride and hydrobromide for four cancer cell strains of stomach cancer (MGC-803), liver cancer (BEL7402), human nasopharyngeal carcinoma (CNE) and human lung adenocarcinoma (A549) are respectively lower than those of nitidine chloride, and are much lower than those of 5-FU (control drug).
Description
Technical field
The present invention relates to 2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridine derivatives, and preparation method thereof, and the pharmaceutical composition that contains the preparation anti-tumor aspect of above-mentioned substance.
Background technology
Tumour is common disease, the frequently-occurring disease of serious threat human health, is one of main disease that jeopardizes at present the human life, and its death has occupied first of all kinds of causes of the death.In three large therapies of malignant tumour, pharmacological agent occupies an important position at present.The overwhelming majority is the compound take the natural antitumor activeconstituents as the guide in synthetic chemical classes antitumor drug, from natural product, seek antitumor guide's product and carry out structure of modification, make it to become focus (the Chinese tumour that anti-cancer agent is current antitumor research, 2007,16(9), 705～708).It is found that generally all there be the shortcoming low to tumor cells selectivity in present cancer therapy drug, nearly all cancer therapy drug also kills and wounds normal cell when killing and wounding cancer cells.Therefore, improve the selectivity of cancer therapy drug, the cancer therapy drug of developing high-efficiency low-toxicity and be the focus that scientists pays close attention to (Science Bulletin, 2001,6,451-460).
The benzo phenanthridine alkaloid is the important morphinane alkaloid of a class, mainly is distributed in papaveracease and the rutaceae.It is that phenyl ring also forms with the phenanthridines ring together from structure, therefore it has four rings, the ring at two ends is aromatic nucleus, middle ring can be that aromatic nucleus also can be the aromatic nucleus of hydrogenation, on non-azo-cycle, be with at least two oxygen containing substituting groups, mostly on the nitrogen-atoms connect a methyl, and they are present in the plant mainly with the form of quaternary ammonium salt, this Alkaloid is because the singularity of its structure has extraordinary anti-tumor activity mostly.
For example the analogue NK109 of white chelerythrine acts on the half casualty-producing concentrations (IC of human cervical carcinoma cell lines S3
50) be 0.05 μ g/mL(Org.Lett.1999,1(7), 985-988); Nitidine chloride acts on human breast cancer cell strain MCF-7, breast carcinoma cell strain HS578T, prostate cell strain DU145, the IC of prostate cell strain MPC3
50Be respectively 40.59,145.0,2.64,78.89ng/mL(Antimicrob.Agents Ch.1999,43(12), 2862-2868).
Summary of the invention
The purpose of this invention is to provide 2 shown in the formula I, 3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridine derivatives, its synthetic method with and the preparation inhibition tumor cell active aspect the application of medicine.
X
-Be independently selected from chlorion, bromide anion, iodide ion, sulfate ion, phosphate anion, nitrate ion, perchlorate, fumarate ion, acetate ion, propionate ion, succinate ion, oxyacetic acid radical ion, formate ion, lactate ion, maleate ion, tartrate anion ion, citrate ion, malonate ion;
The present invention also provides preparation 2,3-dioxoethyl-5-methyl-8, the method of 9-dimethoxy benzo phenanthridines-halogen acid salt, the method comprises: with 2,3-dioxy ethylidene-5-amino naphthalenes and 2-bromo-4, the 5-dimethoxy benzaldehyde is that raw material reaction obtains Schiff's base, with this Schiff's base reduction, cyclisation, quaternized, halo just obtains target product, and reaction formula is:
The present invention also provides a kind of pharmaceutical composition, comprises at least a pharmaceutically acceptable carrier and formula I compound or its solvate.
The present invention also provides formula I compound or its solvate or the above-mentioned application of pharmaceutical composition aspect the preparation antitumor drug.Particularly in the application aspect the preparation treatment solid tumor drugs.The formulation of medicine comprises injection, oral acceptable preparation, local application's preparation, sprays or drops.
Of the present invention 2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines is the derivative of nitidine chloride, has fine anti-tumor activity.By to cancer of the stomach (MGC-803), liver cancer (BEL7402), human nasopharyngeal carcinoma (CNE), four kinds of JEG-3 body outer suppressioning experiments of human lung adenocarcinoma (A549), confirm of the present invention 2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines-halogen acid salt has good restraining effect, wherein to the IC of liver cancer (BEL7402), human nasopharyngeal carcinoma (CNE), three kinds of JEG-3 of human lung adenocarcinoma (A549)
50Below 3 μ M.
New compound 2 of the present invention, 3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridine derivatives particularly its halogen acid salt has significant cytotoxic activity to tumour cell, is expected to become antitumor drug.
Embodiment
The following examples are the preferred illustrative preferred versions of the present invention, and the present invention is not constituted any limitation.
Synthesizing of embodiment 1:2-bromo-4,5-dimethoxy phenyl aldehyde (compound 1)
Methyl alcohol (20mL), Veratraldehyde (1.42g, 8.55mmol) are joined in the round-bottomed flask, slowly add bromine (0.5mL, 9.76mmol), reacted the rotary evaporation desolventizing 1 hour.Under constantly stirring, add entry (50mL), gained mashed prod Büchner funnel suction filtration, water and methanol wash are dry that 1.76g is colourless to yellowish product again, productive rate 84%.M.p.143～145℃，
1H?NMR（500MHz，CDCl
3）δ:10.21（s，1H，CHO），7.44（s，1H，ArH），7.08（s，1H，ArH），3.97（s，3H，OCH
3），3.94（s，3H，OCH
3）。The structural formula of compound 1 is as follows:
Embodiment 2:2,3-dioxoethyl-5-amino naphthalenes (compound 2) synthetic
With dehydrated alcohol (170mL), 2,3-dioxoethyl-5-nitro-naphthalene (1.56g, 7.18mmol) and 10% Pd/C 0.15g join in the round-bottomed flask, pass into hydrogen reaction 8 hours, and filtered, remove ethanol, residue obtained with the silica gel column chromatography 1.11g lavender solid of purifying to get, productive rate 82%.M.p.169～173℃，
1H?NMR（500MHz，CDCl
3）δ：7.28（s，1H，ArH），7.26（s，1H，ArH），7.18（m，2H，ArH），6.65（m，1H，ArH），4.36（s，4H，OCH
2CH
2O），3.97（s，2H，NH
2），
13C?NMR（CDCl
3，125MHz）δ：143.92，143.28，140.94，130.62，124.78，119.90，117.80，113.25，108.20，106.54（10C，2Ar），64.54，64.52（2C，OCH
2CH
2O）；IR（KBr）ν:3838（N-H），3735（N-H），3368，1636（Ar-H），1517（Ar-H），1475（Ar-H），1290（C-O），1252（C-O），1067（C-O），904，864cm
-1；APCIMS?m/z:201.83[M+H]
+。The structural formula of compound 2 is as follows:
Embodiment 3:N-(2-bromo-4,5-dimethoxy α-tolylene)-6,7-(dioxoethyl)-naphthalidine (compound 3) synthetic
With dehydrated alcohol (150mL), compound 1(2.19g, 8.97mol), compound 2(1.68g, 8.97mol) join in the round-bottomed flask, reacting by heating 10 hours, cooled and filtered is used washing with alcohol, obtain 3.05g khaki color solid after the drying, productive rate 82%.M.p.218～221℃，
1H?NMR（500MHz，CDCl
3）δ:8.81（s，1H，CHN），7.94（s，1H，ArH），7.76（s，1H，ArH），7.57（d，J=8.2Hz，1H，ArH），7.33（m，2H，ArH），7.09（s，1H，ArH），6.95（d，J=7.2Hz，1H，ArH），4.37（brs，4H，OCH
2CH
2O），4.03（s，3H，OCH
3），3.97（s，3H，OCH
3）；
13C?NMR（CDCl
3，125MHz）δ:158.40（1C，CHN），152.33，148.87，148.01，144.38，143.74，130.29，127.42，125.08，124.53，118.03，115.51，115.22，112.49，111.43，110.43，108.29（16C，3Ar），64.51（2C，OCH
2CH
2O），56.32，56.23（2C，2OCH
3）；IR（KBr）ν：1592（Ar-H），1564（Ar-H），1505（Ar-H），1465（Ar-H），1288（C-O），1248（C-O），1214（C-O），900，862cm
-1；APCI-MS?m/z:427.96[M+H]
+。The structural formula of compound 3 is as follows:
Embodiment 4:N-(2-bromo-4,5-dimethoxy benzyl)-6,7-(dioxoethyl)-naphthalidine (compound 4) synthetic
With toluene (150mL), compound 3(3.05g, 0.96mmol), dimethylin borine (0.87g, 14.76mmol) add in the round-bottomed flask, then add glacial acetic acid 4mL, react after 1.5 hours, the hydrochloric acid that adds 1mol/L, continue to stir 1 hour, add the sodium hydroxide solution neutralization, rear filtration stirs, filter residue obtains the 2.79g white solid with ethyl alcohol recrystallization, productive rate 91%.M.p.203～204℃，
1H?NMR（500MHz，CDCl
3）δ:7.31（m，3H，ArH），7.28（s，1H，ArH），7.25（s，1H，ArH），7.19（m，2H，ArH），7.07（s，1H，ArH），7.03（s，1H，ArH），4.49（s，2H，CH
2），4.36（s，4H，OCH
2CH
2O），3.90（s，3H，OCH
3），3.78（s，3H，OCH
3）；
13C?NMR（CDCl
3，125MHz）δ：148.94，148.68，143.81，143.33，130.45，124.88，119.75，117.20，115.73，113.48，112.67，105.93，104.05（16C，3Ar），64.55，64.51（2C，OCH
2CH
2O），56.32，56.23（2C，2OCH
3），48.85（1C，CH
2NH）；IR（KBr）ν：3393（N-H），2938，1581（Ar-H），1491（Ar-H），1471（Ar-H），1292（C-O），1260（C-O），1071（C-O），866cm
-1；APCI-MS?m/z:429.82[M+H]
+。The structural formula of compound 4 is as follows:
Embodiment 5:2,3-dioxoethyl-8,9-dimethoxy benzo piperidine alkaloid (compound 5) synthetic
With toluene (50mL), compound 4(0.96g, 2.23mmol), n-Bu
3SnH(1.30mL, 4.68mmol) join in the round-bottomed flask, the heating, will contain AMBN(2,2'-Azobis(2,4-dimethylvaleronitrile) 1.29g, 6.70mmol) toluene (2mL) solution join in the mentioned solution, reacted 12 hours, then add MnO
2(1.35g, 15.52mmol), stirring at room 1 hour is filtered, and filter residue obtains the 0.39g pale solid with the mixing solutions recrystallization of trichloromethane and sherwood oil, productive rate 50%.M.p.276～278℃，
1H?NMR（500MHz，CDCl
3）δ:9.24（s，1H，ArH），8.77（s，1H，ArH），8.23（d，J=8.9Hz，1H，ArH），7.85（s，1H，ArH），7.80（d，J＝8.9Hz，1H，ArH），7.38（s，2H，ArH），4.42（s，4H，OCH
2CH
2O），4.16（s，3H，OCH
3），4.10（s，3H，OCH
3）；
13C?NMR（CDCl
3，125MHz）δ:152.99，149.77，149.47，144.63，144.59，140.46，128.92，128.70，128.07，126.13，122.34，119.58，118.14，113.10，111.07，107.28，101.64（17C，3Ar），64.60，64.48（2C，OCH
2CH
2O），56.10，56.07（2C，2OCH
3）；IR（KBr）ν：1618（Ar-H），1516（Ar-H），1498（Ar-H），1469（Ar-H），1298（C-O），1260（C-O），1167（C-O），850cm
-1；APCI-MS?m/z:347.94[M+H]
+。The structural formula of compound 5 is as follows:
Embodiment 6:2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines-o-nitrobenzene sulfonic acid salt (compound 6) synthetic
With toluene (40mL), compound 5(0.36g, 1.03mmol), ortho-nitrophenyl sulphonyl methyl esters (0.45g, 2.07mmol) joins in the round-bottomed flask, reacting by heating 35 hours, cooled and filtered, solid toluene wash, get 0.49g yellow solid, productive rate 84% after the drying.M.p.307～310 ℃,
1H NMR(500MHz, DMSO-d
6) δ: 9.79(s, 1H, ArH), 8.82(d, J=8.6Hz, 1H, ArH) and, 8.33(s, 2H, ArH), 8.24(d, J=8.4Hz, 1H, ArH) and, 7.87(t, 1H, ArH), 7.81(m, 2H, ArH) and, 7.54(m, 3H, ArH), 4.89(s, 3H, CH
3), 4.45(s, 4H, OCH
2CH
2O), 4.20(s, 3H, OCH
3), 4.02(s, 3H, OCH
3);
13C NMR(CDCl
3, 125MHz) δ: 132.62,131.08,130.32,129.48,122.75,119.37,114.90,114.37,109.09,103.69(23C, 5Ar), 65.11,64.92(2C, OCH
2CH
2O), 57.75,56.81(2C, 2OCH
3), 51.91(1C, NCH
3); IR(KBr) ν: 2254(C=N), 1653(Ar-H), 1558(Ar-H), 1541(Ar-H), 1507(Ar-H), 1026(C-O), 1001(C-O), 826cm
-1ESI-MS m/z: remove positively charged ion formula weight behind the o-nitrobenzene sulfonic acid root: 362.16.The structural formula of compound 6 is as follows:
Embodiment 7:2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines hydrochloride (compound 7a) synthetic
With compound 6(0.49g, 0.86mmol) and 30mL hydrochloric acid join in the round-bottomed flask, stirring reaction 3 hours filters, wash with water, after the drying the 0.29g yellow solid, productive rate 85%.M.p.295～296℃，
1H?NMR（500MHz，DMSO-d
6）δ：9.89（s，1H，ArH），8.83（d，J=9.1Hz，1H，ArH），8.34（s，1H，ArH），8.33（s，1H，ArH），8.25（d，J=9.1Hz，1H，ArH），7.90（s，1H，ArH），7.79（s，1H，ArH），4.92（s，3H，CH
3），4.49（d，J=2.3Hz，4H，OCH
2CH
2O），4.23（s，3H，OCH
3），4.05（s，3H，OCH
3）；
13C?NMR（CDCl
3，125MHz）δ：206.88，158.73，152.12，151.06，145.88，144.57，132.54，131.32，130.28，124.53，120.21，119.38，119.31，114.88，114.36，109.08，103.70（17C，4Ar），65.11，64.92（2C，OCH
2CH
2O），57.78，56.81（2C，2OCH
3），51.92（1C，NCH
3）；IR（KBr）ν：1652（C=N），1507（Ar-H），1436（Ar-H），1020（C-O），1001（C-O）cm
-1；ESI-MS?m/z:361.91[M-Cl]
+。The structural formula of compound 7a is as follows:
Embodiment 8:2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines hydrobromate (compound 7b) synthetic
Make 2,3-dioxoethyl-5-methyl-8 with embodiment 7 same methods, 9-dimethoxy benzo phenanthridines-hydrobromate 7b, productive rate 86%.
Embodiment 9: the mensuration of anti-tumor activity
Use mtt assay and tested 2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines-hydrochloride 7a and hydrobromate 7b are to the half casualty-producing concentrations IC of cancer of the stomach (MGC-803), liver cancer (BEL7402), human nasopharyngeal carcinoma (CNE), four kinds of JEG-3 of human lung adenocarcinoma (A549)
50Used people's Gastric Cancer MGC-803, human hepatocellular carcinoma BEL-7402 cell, human nasopharyngeal carcinoma CNE cell and human lung adenocarcinoma A549 cell are provided by Shanghai Inst. of Life Science, CAS cell resource center.Modified form RPMI-1640 substratum is the Hyclone product.Foetal calf serum is available from Hangzhou Sijiqing Biological Engineering Material Co., Ltd..5 FU 5 fluorouracil (5-fluorouracil, 5-FU) is available from the rising sun East Sea, Shanghai general medicine company limited liability company.Microplate reader: Bio-Rad, USA.
The logarithmic phase cell is inoculated in 96 orifice plates, is divided into negative control group (Control, RPMI 1640), positive controls (5-FU, 10 next day
-4MolL
-1) and reagent group (0.01～100 μ molL of 5 10 times of gradients
-1), dosing is established 4 parallel holes for every group.In finishing to cultivate (24h, 48h and 72h) front 4 hours, add 5mgmL
-1MTT.After finishing to cultivate, the careful suction abandoned supernatant liquor, and every hole adds 100 μ LDMSO, hatches 15 minutes for 37 ℃, detects the absorbance (absorbance value, A value) in each hole in microplate reader 490nm.Compound to the inhibition proliferation activity formula of tumour cell is:
Inhibiting rate (%)=(A
Negative control-A
Compound)/(A
Negative control-A
Blank) * 100%
With inhibiting rate concentration is mapped, release regression equation, inhibiting rate is that 50% concentration is IC
50By the experiment of cell in vitro poison, obtain following result:
As can be seen from the above table, of the present invention 2,3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridines-hydrochloride 7a and hydrobromate 7b are to the half casualty-producing concentrations IC of liver cancer (BEL7402), human nasopharyngeal carcinoma (CNE), three kinds of JEG-3 of human lung adenocarcinoma (A549)
50All be lower than nitidine chloride, more be significantly less than 5-FU(contrast medicine), have fine anti-tumor activity.
Claims (6)
1. 2 shown in the formula I, 3-dioxoethyl-5-methyl-8,9-dimethoxy benzo phenanthridine derivatives,
X
-Be independently selected from chlorion, bromide anion, iodide ion, sulfate ion, phosphate anion, nitrate ion, perchlorate, fumarate ion, acetate ion, propionate ion, succinate ion, oxyacetic acid radical ion, formate ion, lactate ion, maleate ion, tartrate anion ion, citrate ion, malonate ion.
2. prepare 3-dioxoethyl-5-methyl-8, the method of 9-dimethoxy benzo phenanthridines-halogen acid salt, comprise: with 2,3-dioxoethyl-5-amino naphthalenes and 2-bromo-4,5-dimethoxy phenyl aldehyde are that raw material reaction obtains Schiff's base, with this Schiff's base reduction, cyclisation, quaternized, halo just obtains target product, and reaction formula is:
3. pharmaceutical composition comprises at least a pharmaceutically acceptable carrier and such as the defined formula I compound of claim 1 or its solvate.
Such as the pharmaceutical composition of the defined formula I compound of claim 1 or its solvate or claim 3 in the application aspect the preparation antitumor drug.
5. such as claim 4, the application aspect preparation treatment solid tumor drugs.
6. the formulation such as medicine as described in claim 4 or 5 comprises injection, oral acceptable preparation, local application's preparation, sprays or drops.
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| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | A kind of synthetic method and antitumor application thereof of phenanthridines class nitidine derivative |
| CN109942590A (en) * | 2019-04-12 | 2019-06-28 | 云南民族大学 | A kind of preparation method of Nitidine Chloride |
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| CN104356139A (en) * | 2014-11-21 | 2015-02-18 | 刘华钢 | Synthetic method of nitidine chloride |
| CN105820119A (en) * | 2015-07-06 | 2016-08-03 | 盐城工学院 | 5,6-dihydrobenzophenanthridines derivative and preparation method thereof |
| CN105820119B (en) * | 2015-07-06 | 2019-04-02 | 盐城工学院 | One kind 5,6- dihydrobenzo phenanthridine derivatives and preparation method thereof |
| CN107502588A (en) * | 2017-10-16 | 2017-12-22 | 吉林省太阳鸟再生医学工程有限责任公司 | A kind of method that separation prepares dental pulp stem cell |
| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | A kind of synthetic method and antitumor application thereof of phenanthridines class nitidine derivative |
| CN109369772B (en) * | 2018-12-19 | 2021-01-05 | 桂林理工大学 | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives |
| CN109942590A (en) * | 2019-04-12 | 2019-06-28 | 云南民族大学 | A kind of preparation method of Nitidine Chloride |
| CN109942590B (en) * | 2019-04-12 | 2021-07-02 | 云南民族大学 | Preparation method of nitidine chloride |
| CN111467347A (en) * | 2020-04-30 | 2020-07-31 | 河北医科大学第二医院 | Application of benzophenanthridine alkaloid compound in preparation of calcium-activated chloride channel blocker encoded by ANO1 |
| CN113480552A (en) * | 2021-06-04 | 2021-10-08 | 中国农业科学院北京畜牧兽医研究所 | Compound and application thereof in improving animal rumen microbial fermentation |
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